The overall objective of this work is to enhance the understanding of prostate cancer initiation and progression. The main goal of the present proposal is to characterize new models of hormonal carcinogenesis in the mouse prostate. These experiments will use retinoblastoma (Rb) gene-knockout and conditionally deleted-Rb mouse prostate as a target for hormonal carcinogenesis. Experiments will examine the ontogeny and histopathology of carcinogenesis (aim 1), the precise role played by sex steroids (aim 2) and the specific epithelial cell type targeted by hormonal carcinogens (aim 3). A panel of cell strains will be derived from the tumors which are generated. Their behavior in vivo will be characterized and they will be subject to genomic analysis to identify common genetic lesions associated with prostate cancer (aim 4). Data from these studies will be used to identify candidate genes involved in prostatic carcinogenesis. The central hypothesis is that the progression from normal histology to cancer seen in mouse prostatic tissue lacking expression of the Rb tumor-suppressor gene is a good in vivo model of human prostate cancer. This project will use two new in vivo models of prostatic carcinogenesis. The first is a tissue recombination model based upon prostatic epithelium derived from the Rb-knockout mouse. The second model is a conditional deletion of Rb in the luminal epithelial cells of the prostate utilizing cre-lox technology. In both models a combination of testosterone and estradiol will be used to initiate the formation of prostate tumors. Prostate tumors will be used to generate a spectrum of cell lines representative of the stages from normal prostate to hormone- independent prostate cancer. These cell lines will serve as a source material to examine genomic lesions associated with prostate cancer progression. The following specific aims will be pursued. Specific Aim 1 Characterization of tumor progression in Rb-deficient mouse prostate under the influence of testosterone and estradiol. Specific Aim 2 An examination of the roles of testosterone and estradiol in hormonally induced prostatic carcinogenesis in the Rb-deficient mouse prostate Specific Aim 3 Generation and Characterization of ARR2Pb-cre RbloxP/loxP mice. Hormonal Carcinogenesis in ARR2Pb-cre RbloxP/loxP mice. Specific Aim 4 Isolation, phenotypic and genomic characterization of Rb-deficient cell strains.